CA2112127A1 - Novel process for aromatic bromination - Google Patents

Abstract

2112127 9302036 PCTABScor01 A novel procedure for bromination of aromatic moieties utilizes N-bromosuccinimide or dibromodimethylhydantoin in an aqueous alkali medium. The bromination procedure is employed for the preparation of an intermediate used in the preparation of remoxipride, an antipsychotic compound.

Description

WOg3/02036 P~T/~S9~0~901 ~ 1 ~127 , r :
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. ~

:1 5 10~ ~:TITLE OF THE INY~IC~
NOVEL~PROCESS:EOR AROMATIC BROMINATION~ :

; RELAT~D~APPLIC8'~ION
The pre~ent patent application i B a con~i~uation-in-part~of copendin~;~applic-ation Seri~al ~:
No.~730,364;,;fl1e~d~;July:15,~1991 :BA~K~ ND~:~F TH~INV~NTI~
N-Bromosu~ imide~ NBS) i~ a well:~ ~n:~ ~ khe~i~e or i~ ea~ent~:w ich~is useful lD~;bro ination:~and/o:r:~ :
`oxid~atiQn o~:~a~w:ide:~a~ie~y:or~ganic moietie~:under a :
wide ~ariet~y~of reaction conditi s.~ ~:A~re~iew~ of~
chemietry~:is~f~ound~in:J~.S.~Pizey~ Syntheti~Reag:ents, : : ~
ol.~;2i~John~Wiley? New York,~ ~1974?: ~at pages 1-63. ::
hile~ ~S~bromination8~0f~aromatic moietie6~have~ been~
p~rfo~med in`polar ~nd:~:non-polar o~ganic ~ol~ent:æ~and in~:aqueous: aci~dic solution,- there;have ~een no ~
rcpo~ts~of~NBS:brcm:inàtions utlilizing aqueou's alkali ;

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w093J02036 PCT~US92~05901 ~ ~ 1 ~ 7 . 601utîons as the reaction medium. Utilization of ,5, such a basic medium has the advantage in that i hydrogen bromid~e, generated in the reaction, is scavenged by the sol~ent, thereby reducing the po~sible side reactions associated with its pre~ence in soluti~n. Multlple brominations are also not ~, obser~ed.
. Dibromodimethylhydantoin (DBDM~), while not as widely employed as NBS, is a versatile organic 10 reagen~ (for a review see : Reed , R. A., .Chem. Prod ., :~:; 23, 299 (1960)). It offers the advantage of being more stable and less costly on a bromine equivalent .. basi~ than NBS. Pre~ious disclosed bromination~ of aromatic sub~tra~ed using DBDMH were run in refluxing ~CCl4 or ~C13. DBDM~ is al~o used as a pool : ;;: disin~ectant. ~ : :
Remoxipri~de I ((S)-3-brQmo-N-t(l-ethyl-2-pyrrolidi~yl)methyl3-2,6-dimethoxybenzamidej, ~h~
below, is:a k~own~an~ipsychotic agent (U.S. Pat. No.
20~ 4,232,037). Prep~aration of remoxipride typically : involves a convergent synthe~i~ wherein a ~uitably activated 3-bromo-2,6-dimetho~ybenzoic ~cid II is coupled with the enantiomerically pure aminomethyl :: pyr r oli d ine III .

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i ~ ~" ', WO 93/02036 PCr/US92/0~01 ~ 1 ~ 1 2 7 Z + H

Br : OCH3 II III

~ ~ :
~ ' ~ : , :

:20~ C2H5 Br: ~ OCH3 ~ ~ ~

Z = ~ClI VATI NG GROUP
, ,, ~

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:;:::~: :

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WO 93/0~036 PCl /VS92/0~901 ~112127 4 ; ~

Preparation of Intermediate I~a the precur~or of compound II typically in~olves brominat~on of commereially a~railable 2, 6-dimethoxybenzoic acid employirlg bromine and 5 dioxane ~s sho~al be~ow.

CCOH COOH .;
~0 1 ~
~`,~ Dioxl~ne/13rorrin~

IVa ;; ;.
;.
''' -' ~`, ` ", Although good yields of the Intexmediate IVa ;
are obtained ~rom the reaction, æeveral impuritie~
shown be:Low, resu1t f~om the further reac~1on os~ the /; ;
produ~t and bromia~e and/oF the hsrdrogen bromide ;;~
gerlerated in ~he reactio : : ' ,, ~ ~, .

;

' ~
.

~': :

W0 93/02036 ~ 12 7 PCI/US~2tO~901 ' , .

, ', ' ,~

; COOH
.. S ~ ~ CH30~J~DH :

~r COO~ : ~ COO}I
O ~ 3y~oc~ .~H3o~oH

r~Br ~ Br~i3r The~ins~ant ~invention~ ~p~r~vide~ aD~ improved~
romin~ti~n ~p~:o~és~s~ :f~or ~he preparation of brominated aromatic~compounds~which~result~in~quantitatively:
2Q ~ fewe$:~o~ t:he~i;mpurities::~that are aæsoclated uith~ ~ ~
pr:e~iou~s disclo~e~d:~bromination;proces~es. :~ :
:The:~ sta~t inyention a~sa~ pr~videg a novel reaction:~co~dition`for~bromination~;of:aromatic ~ :
compou~ds~wi:th:;N-bromosuccini2lde or~
Z5 ~ dibrom~dimethylhyd~antoi~n~uherein the solvent iæ an ~ :
aqueous alk~li 801uti~n.
urther, the instant in~cntion to provides an impro~ed pr~ces~ for the preparation of 3-bromo-Z~6-dime~hoxybenzoic:acid~ha~in~ higher ~3~0~ yields and fewer impurities than processes previo~sly -~ ~ nown in~the ~rt.
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s DETAIL~D D~SCRIPTION OF T~E I~ IQN
The pre~ent in~ention provides a nove1 process for the preparation of a bromoaromatic '~
~5 compound, having the ~ormula ~V:
~-- R
R1 ~ R3 Elr J~R4 IV
~ :
::: :
, lS wherein ; ~ ~

Rl,~RZ, R4, and~R5 are independently:selected from:
: (a)~hydrogen,~
b) Cl-C6-alky1, 2~0~ (c) C1-C6-a~1koxy,: ~;

(e) -~02E~
(f) -C02(Cl-C6-a1~y1) N(Cl-C6-alkYl)2t : - or Rl, R2, R3, R4~, or ~5 on adjacent r~lng carbons may be combined to form a O-(C~2)n-0- ~esidue;
. .
provided that at least one of R1, ~2, R4, or R5 is ~ o -C0 :
,~ ,., R3 is C1-C6-a1koxy or -N~Cl-C6 a1kyl)2. or R2 and R3 : or ~3 and R4 are combined to form a -0-(C~2)n 0-residue; and :'~
~r7S,~

W093/02036 PCT/VS9~/05901 2 1 1 ~

n i~ l to 3;
.~ .
: which comprise~:
treating an aromatic compound o~ the formula V:

: R2 1 0 ~KA\

~: :. ' V
wher:ein:the æubstituent Rl, R2, R3, R4, and R5:are :15 ~ as:~-described her~ein above; ~ ~ :
in~;~an~aqueous:alka1i ~olution w;ith~a~brominating~agent selected from~
20~ a) N-bromo8uccin:imide, and~
(b) l,3-dibromo-5,5-dimethylhyda~toin;

at a:t~empe~ature and for a length of time sùfficient to:~ptimally con~er:t th~;compou~d~:o~formula Y to the :2~5~ comp~ound 0f formula IV or a sa~t thereof; and then optionally treating the reaction mi~ture with an acid to ~orm theicompounid of formula IV. ~ I

~ :

:~ : ~ :
,, ~ ::
~' ~ ' , .:

',!i.,'.

W~93/02~36 PCT/US92/05901 ? ~
. .~ .~. ;, ~ ~ I -- 8 The term "aqueous alkali solution~ includes solution of an alkali base in an aqueou~ solvent and the like.
. ,,~ .
;~ The term "alkali base" include6 strong S alkali ba~es, which include sodium hydroxide1 lithium hydroxide, potassium hyd~oxide and the like. A
.
;~ . preferred alkali:base is sodium hydroæide.
The term 'laqueous 801~ent" include~ wate~
and ~olutions of wa~er and a water miscible co-solvent(s). The term ~water miscible co-sol~ent1' includes low-molecular-weight alcohols, dimethoxy-ethanej tetrahydrofuran and the like. A pre~erred , aqueous ~olvent is water.
The te~m "low-molecular-weight alcohol"
~:~includes~hydro~yalkane~compound~ having~from 1 to 4 carbon~atoms~and~:includes branched and ~traight hain alcohols. The term includes~methanol,:ethanol,~
is~-propanol:~and~the like~
:The~term~"temperature , . .~ ufficieDt to 2~Q ;:~:opt;imally convert~the~eompound~:of~t~he~formula ~to a :salt~of the compound of the~formula IV1' repre~ent~ a temper~atùre ~ufficiently high~to main~ain con~er~ion of~:the star~ing:material V but al~o ~ufficien~ly low to avoid~-;decomposi~ion of`the ~tartin~ material and :25 ::-~the~pr:~duct. The t~rm includes te:mper:atures between 0 ~ and 30~C. A preferred temperature ia between 23 and 29~C.

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`- WO 93/02Q36 ~ PCr/US92/05901 The term ~length of time sufficient to - optimally convert the compounds of the formula Y to a -~salt of the eompound of the formula IV~' repre~ent~ a period of ti~De ~uff iciently long to convert the 5 maximum amount of the ~tarting material to the salt of the compound of the f ormula IV. The term includes times of 1 to 40 hours. A preferred length of time is a time length between 4 and 25 hour~s.
~` The term ~a salt of the compound of formula 10 ; IV~ includes the salt of a carboxylic:acid moie~y of the product IV (if such a moiety~ :i8 p~re:æen~) which corresponds::to ~he alkali base employed in ~he a~ueous alkali solu~ion. The term includes the odium salt, lithium salt, potassium sal~ and the 15 like~
The term ~acid~ includes anhydrous acids and aqueous:acidic æolution~
- The term ~'lanhydrous acid" includes gaseous:
miner;al acids such:~as hydrogen;bromide, hydrogen~
20~ :chl:oride~and the like.
The term~"aque~us acidic solution~ inc;ludes~
solutions of a mineral acid or ~ulfuric acid in an aqueous æolvent.: The term "minera~l acid:~ include~
: hydrogen:chloride,~hydrogen b~omide and the li~e. A
2s ~preferred aqueous acidic solution i~agueous : : hydrobromic acid.

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., W093/0203~ P~T/US92/~S901 1 ~ 7 One embodiment of the process of the in~t~nt invention is that process wherein the brominati~g agent emplsyed is N-bromosuccinimide in an amount selected frol~ a value in the range between 1.0 to 1.5 molar e~ui~alent~ with respect to ~tarting aromatic compou~d V.
In a clas~:of this embodiment i~f the process wherein the amount of the alkali base in the aqueous :
alkali ~olution employed is selected from a value in the range~between 1.0 and 3.5 molar equivaIents with . respect io ~tarting aromatic compound V.
In a ~ubcla~fs of this class of the instant : invention i~ ~he process wherein the ratio of the molar equivalent~amount o~ alkali base remaining after any a:cid~:moiety present in the ~tarting aromatic compound~V ha~ been neutralized to the molar : equivalent of N-bromo~uccinimide utilized is~elected from~a value in ~the range between 1.0 and 1.25.
In anot~er:clas~ of thi~ embodiment is the 2~ procef~s of the instant invention:wherein the acid treate:d reaction mi~ture is cooled and~filtered:to pr~ovide the compound of the formula rv.~
In another clas~ of thss embodimen~ i~ the prccess o~ ;the ins:tant invention wherein the acid treated reaction mi~ture is eætrac~2d with a suitable organic sol~ent which after washing, drying and:
evaporating to dryrless provides the compound of the crmula IV.
Another embodiment of the instant invention 3~ that process wherein the brominating agent Jf: ~ employed ig dibromodimethylhydantoin in an amount :l ~ gef~ected f~om a value in the range between 0.505 to fi :
f i!
..,~
~, ' W093/~2036 PCT/US92/05901 0.55 molar equivalents with respect to starting ~romatic compound ~.
In a class of this embodiment iæ the process ), wherein the amount o~ the alkali base in the aqueous alkali ~olution employed is seleeted from a value in the range between 1.01 and 1.1 molar equi~ale~ts with respect to starting aromatic compound V.
In a ~ubclass of this class o~ the instant ~: invention is ~he process wherein the ratio of the molar equi~alent amount of alkali base remaining after any ~cid moiety present in the starting aromatic compound V-ha~ been neutralized to ~he molar :: equivalent of dibromodimethylhydsntoin utilized is : selected frQm a ~alue:in the range between 0.1 and lS : 1.25 : ~ ~
One embodiment of the instant invention is ;the:process for the preparation of~a~bromobenzoic ac~id, having~the;f~rmula IVa:

~ :: : : CO2H

CH35 ~ CH3 ^ : Br : :

: : IVa 3~

::~ "
, -,, , ., : " ~, ~, ' ' Wos3/02036 PCTlUS~2tOS90~

2 Ll ~ ~ 27 12 -which comprise~:
' treating a benzoic acid of the formula Va:
.. i.
: ;; .-i, ~ ~ CO~H
d3CO~ "OC}~

, : 1 0 ~a in an aqueous alkaIi solution ~. ! "
WIT~N-bromosuccinimide at a tempera~ure and~ for~a :leng~th of time sufficient to optimally conYert the ::c~mpound s~:formula Va to the compound of formula IVa :
: ::or ~a~; ~alt of the~compound of formula IVa; and then optionally::treating the reaction~mixture ~ith an acid,~

One cla~æ of this embodiment of the process : o~:~he:instant invention is th~at process wherein the : : amount ~of N-bromosuccinimide employed:is selerted ;25~ from a ~alue in the~range betweer~ l.O to l.~ moIar equivalents with respect to starting 2,6-dimetho~ybenzoic acid.
In!a~subclass of this embodiment is the-~ ! "
process whereln the am~unt~of the al~ali base in ~he ~: : 30 squeous ~l~ali solutio~ employed is selected from a Yalue in the range betw~en 2.0 and 2.5 molar . equivalen~ with ~espec~ to starting :,i 2~-dimetho~ybenzoic acid.
~, ,:,.,;, ,,,.,.,~
s ..- ~
"~1 :
' l ~,~

WO93Jo2036 PCT/US92/05901 2~ 127 ; Exempli~ying thi~ subclass of this cla~s of the instant inYention is the process wherein the ratio of ~he molar equivalent amount of alkali base remaining after the acid moiety of the 2,6-dimetho~ybenzoic acid has been neutralized to the molar equi~alent of N-bromosuccinimide utilized is selected from a value in the range between 1.0 and . 1.25.
In another ~ubclass of this ~mbodiment i~
l~ the process of the instant invention wher~in the acid : treated reaction mixture is cooled and filtered to provide the compound o~ the formula IVa.
In another subcla~s of thi~ embodiment is :: the process of the instant in~ention wherein the acid treated reacti~n mi~ture i~ ex~racted with a ~uitable organi:c ~olve~t which after wash:in~, drying and evaporating to dryness provide~ the compvund of the ~ ~ ~formula ~Va. :

; 20 The following ~ynthetic Scheme 1 il~u~trate~
a reac~ion ~equence in which the proceæs of the instant inv ntion~i~ employed. It is under~tood that this scheme is meant to be illustrati~Je and i~ not : limiting.

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,.
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W093/02036 PCT/US92/0~901 21 1~v~27 - 14 _ SC:E~EM~3 1 ,.

~2 bronL~ation ~2 R~ gone, R

~ : Li, or K R5 : ' 10 V IV

n words relative to the equations, the aromatic~ compound of the formula Y iæ dissol~ed in an aque~us alkali:~o1:ution containing a excess amount o~
e~uivalents of base,~uch ~s aqueous:NaO~ ~olution, : aqueous ~0~ solution, methanolic aqueous NaO~ and the like. The olution is then treated:with a ~uitable brominating age~t:,~uch as ~-bromosuccinimide or~
1,3-dibromo-5,5-dimethyl- hydantoin, and the reaction mixture is stirred~at room temperature ~or:a period - of time,;such as 2-hours to 24 hours. ;~The react on mixture ii~ then tested by a pota~ium iodide starch paper test (SPT) tstarch iodide:tes~ paper that has been wetted with agueous acetic acid; l/l; v/v)] a~d if the test is positive, an oxidan~-neutralizi:~g alt, such as ~od!ium sul~ite and the like, ls added.
;~ The reaction mixture is th~n treated with an acid or an acidic aqueous solution and cooled in an ice ~;~:j bath. If the : .

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.

WO 93/02036 Pcr/us92~o~9o 1 product ~ormed is insoluble in the work~up Folution, f iltration of the mixture provides the crude psoduct ~i IV which may be used as is in a subsequent reaction -3 or further purified. If isolation by filtration i~
S not appropriate a standard organic sol~rent extracti~e work-up roay be employed.

The following synthetic Scheme 2 illustra~es a reaction sequence in which the process vf an 10 embodiment of the instant in~rention is employed. It is understood that this scheme is meant to be ~; illustrative and is not limiting.

: ~ 15 .

: 2 0 ,.

, ~: 2 ' .
:~. 3D
~,1 ' : ".

;~' ^:' "
~''v' ,., ,~, ,", ' ...

WO ~3/0~036 PCr/U592tO59~1 ~12127 - 16-S~ E 2 . .

.
S CO2H ' CO2M
CO 1 OCH3 H~CO~ 1 ,OCH3 aqueous M- Na, Va Li, or ~ /
1 ~ ~ / O

C02M ~ ~3r-N~
H ,CO~,OCH3 ~ ~ ~ Br /~

20 ~ K3C0~X~I3 ~ ::

Br J~J
: : : : : I Va :
:25 :' ~ :

, , : 3 0 .., :
~.
.

~ ::

,. . .
,~
,,1 ~ Z127 In words relative to the equations, `. 2,6-dimethoxybenzoic acid Va is dissolved in an aqueous alkali solution containing an e~ce~s amo~nt of equi~alents of ba~e, ~ch as aqueous NaO~
solution9 aqueous ~O~ solution and the like, to provide a alkaline solution of the salt VI. The solutio~ is then treated with N-bromosucci~imide ~j (NBS~ and the reaction mixture is stirred at ~oom temperature for a period of time, such as 2 hours to 24 hours. ~The ~eaction mixture is then tested by a potassium:iodide starch paper test (SPT) tstarch lodide te~t paper that has been wetted with aqueous : acetic acid; 1/1; ~Jv)} and if the test i~ positive, n oxi~dant- neutralizing salt, ~uch as sodium sulfite and the:like, i~ added. The reactio~:mixture i~ then treated;with an acid or`an acidic aqueou~ EolUt ion ~
and:co;oled~in an ice bath. Filtration:of the miæture provides the crud~ product IVa which may be used as :: is:~in a~ubsequent reaction or further purified.
; X~20 ~ The:following ~ynthetic Scheme 3 illustrates a~reaction ~equence~i~ which the~proce~ of the:
: instant in~ention is employed in the synthe~is o~
, ~
remo~iprid~e. It is understood that this ~cheme:i~
: meallt to be illu~tr~tive and is not limiting ~ , '~:' :~
:
"
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:i WO 93/02036 P~/USg2l05901 ..

` - 18-H~ C2~35~

O H
~i L-l?rc-llru- VIIl ~; ' : , l G ~ H
X : IX
. :

: V~I C2 3 C ~ ONH

r C CE~ C2~

E~DXI PRI DE CRUDE

:
~ ;
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w~93/02036 PcT/vss2/os9ol ~ r 1 I~J 1 2 7 In words rela~ive to the equations, the aminomethylpyrrolidine component VII of remo~ipride , is prepared from enantiomerically pure L-proline i YIII. To this end L proline is esterified and the ester treated with ammonia in a ~ui~able ~olvent, such as methanol 9 ethanol and the li~e, to pro~ide the amide I~. The amide i~ ring N-ethylated by treati~g it with an aklylating agen~ such as ethyl bromide and the like, in the pre~ence of a ba~e, 6uch lo as potassium carbo~ate, sodium carbonate, and the like, in a suitable solvent such as ethanol. The amide ~ i~ subsequently reduced with a suitable reducing agent, æuch as lithium alumi~um hydride and the like, to provide compound ~
The bromodimethoxybenzoic acid IYa, prepar~d a~ descr~bed in Scheme:2, is treated with an ~ ~ .
.ac~ivating re:agentj ~uch as thionyl chl~ride, ~: : carbo~yl~diimida~ole a~d ~he like, to~provide an activated acid wh;ich i~ reacted, without i~olation, with compound:~II, to provide ~rude remoxipride I.
The in~ention is furthe~r defined by :reference to the following Example~ 1 through 4, which are meant~to be illustrative and not limiting.
Example 1, Method:F, is provided as repre~entative of previouæly known:preparation~ of the intermediate IVa, and is included for comparl~on with the proces~
~:- of the embodiment:of the instant invention. All t~emperatures are in degreés Celsius. Ail purity -~. : percentages of the crude product are we:ight :~ 3b perçentages a~d were determined by HPLC (YMC AQ-301 column (S-5 12~A ODS) rever~e phase; mobile pha~e:
s8% o 07M p~ 1.8 phosphate buffer, 487O C~3CN; 225 nm ~ '1 .:J

.. ..
,,," - ., -, .,, ", - ., .,, ", ., , ,, - , ,, . ,, . ~ , ` W093/0~036 PCT/US92tO5901 21~ 21~7 2~ -. detection) and yield~ of the desired product are i given based o~ pure mono-brominated product. All impurity percentages disclosed were determined by ~PLC and are area percentage6 relative to the desired r product.
i .. ~ ~

, ~ :
Prep~ra~isn of 3- Br~mo 2.6-dimethoxvbenzoi~ Acid : Method A:: Preparation Usi~g N-Bromosuccinimide and A~ueQus Sodium ~ydroxide ~t 2 hourg 10 mi~ u~icn ; A 500 mL~round-bottomed 4-neckét:24/40 ST:
S react~io~ ves~el, ~i~téd with a mechanical ~tirrer and di:gitâl~ thermometer:,~was charged with~8:.0 grams of powde:re:d 2,6-dimetho ~ benzoic acid ;(DMBA) (Aldrich-99%, 43.473 mmol), 50 mL of:deionized water nd 18.25~mL~(2.1 equiv.) of aqueous 5N NaOH ~oln.
20: ~ The~mi~ure ~as stirred, di~solving the~acid and: t~ne :temperature ~ose t:o 30C. The:s~olution~wa~:cooled to C with ~n ice water bath and mai~tained at that temperature~. Then 8.20 grams~of powdered ~ :
N-~romosuccinimidc (Aldrich ~7P)~ was added with : brisk ~irring to:the old ~olution. The reac~ion ~: temperature rose to 8C o~er two minutes then cooled back to 4C over an add;tional 4 m~inutes. The cooling b th was removed and the reaction was allowed to warm to room temperature reaichin~ 21C a~ter 0.5 hr. and Z6C after about one hour. The temperature ro~e to 27 to 28~C ~or the remaining reaction time.
The total time since NBS additio~ was 2 hr. 10 min.

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: , ,, W093J02036 f~ 7 PCT/USg2/o~gol . The reaction at this point ga~e a po~i~ive potassium iodide ~tarch paper test (SPT). The reaction wa~ then ~reated with 0.5 gm Na2SO3 which ~=. ' resulted in a negative SPT. The reaction was diluted with 50 mL vf water and was treated, in portion~, with 12 mL concentrated aqueous EBr (2.43 equi~.) causing precipitation of the product. The mi~ure was cooled ~o ice bath temperature and filtered off (fritted glass funnel, M porosity). The solid was ;; 10 slurried and washed in portions with 125 mL of ice cold pure water:(the pE at the end of the filtration ro~e to 3C. The precipitate was suction dried under -: a nitrogen stre~m and then dried overnight under high acuum~at 75C. ~The product wei~hed-9~95 gm. which lS by ~PLC analysi~ contained 1.1 wt.% of unreacted ~: .
tarting material/1;.4% yield and 97.9 wt.% of the desi:red~monobrominated product/85.8% yîeld: and:no : dete~ctable water:by Karl Fischer: ~ ) titration.

~ Method~B: Preparation Using N-Bromosuccinimide and Aqueous Sodium Hy~dro~ide at 4 hour 20 min.
: Durati~n A 5 liter round bottomed 4 neck 24/40 ST.
reaction ves~el, fi$ted with a mechanical stirrer and digital thermometer,:was charged with 104 grams of po~dered 2,6-d:imethoxybenzoic acid CAldrich 9~%), ~: (565 mmol) 255 mL of 5N aqueous NaO~, (1275 mmol, : 2.256 equiY.~)':and 650- mL of water. Thë mixture was irred to d~i~solve the DMBA then cooled to 0C with ~ 3~ an ice/MeO~ bath. To the reaction mixture was added ; ~ : : powdered N-bromosuccinimide (Aldrich 99%) ~121.9 grams, 1.2 equi~.) in portions: ninety grams of NBS

-: ~

L h~; - 22 -was add~d over two minutes and the reaction temperature rose to 5C then another 31.9 grams was added. The reaction mixture was cooled to 2C then the cooling bath was remo~ed allowing the reaction temperature to rise to room temperature. After 4 hr.
and 20 min. the reaction ga~e a positive SPT. The reaction mixture was treated with 8 grams of sodium sulfite which resulted i~ a negative SPT. The insolubles were fil~ered from the reaction mixture and the filtrate returned to the reaction vessel. An additional 65Q mL of water was added to the filtrate. Concentrated 48% aqueous hydrobromic acid (167.`57 mL, 2.6 equi~ was added to the reaction mixture~oYer 1 min. whieh caused the product to precipitate . The ~;:thick reaction mix~ure wa~ diluted with~ SOO~; mL of~ water and cooled to 0-5C, then ered~through a 3 liter filter funnel with a (M) porosity~f:rittèd di~k. The solid~ was washed with an:
additional 1150 mL of water in portions. The 15ast filtrates~gave a weak positive test fo~ bromides.
The solid~ was suction dried under nitrogen then under hi~h Yacuum at 60:~C overnight:to provide 140.8 grams of the désired p~oduct (92.7% yield; 97.1% w~.% pure containing 0.29 wt.% of unreac~ed starting material and no detectable water by RF titratio~).

Method C: Preparation Using N-Bromosuccinimide and Aqueo1us Sodium ~Iydroxide at 21 hour 34 min.
Vw~ation ~ n : JV A 5 liter round-bottomed 4-necked 24/40 ST.
~'' reaction ~es~el, fitted with a mechanical stirrer and ~digital thermometer. was charged with 104 grams of ~/~

: WOs3/02036 PcT/~ss2/ossol 1 2~ .127 .~ .
, powdered ~,6-dimethoxybenzoic acid (Aldrich 99%, 565.1 mmol), 255 mL of 5N aqueous NaOE (1275 mmol, :~ 2.256 equi~.) and 650 mL of water. The mixture was stirred to diæsolve the DMBA then cooled ~o 1C. To . 5 the reaction mixture was added powdered s, N-~romosuccinimide (121.93 grams, Aldrich 99%, 1.2 equiv~ in por~ions: about 90 grams was added o~er three minute~ and the reaction temperature rose to 8OC. The reaction temperature then decreased to 6C
and the remaining NBS was added. The temperature rose again to 8C and then the reaction mixture cooled down to 3C and the ice/water cooling bath was removed. The temperature of the reaction mixture wa~
allowed ~to ri~e t~room temperature. ~:ter 21 hr. 34 15 min. the reaction ~mixture gaYe a weakly positi~e : : SPT. The:: reaction mixture~ is treated with 2 . 0 gram~
of ~odium~:sulfite which resulted in a negative SPT.
The reac~ion mixtu~e was filtered:to remove a ~.mall amount:of~ insoluble matter. The fi~tered reaction 20 mixture was returned to a clean 5 litz r reac~ion essel and diluted~with 650 m~ of water. To the stirred reaction mixture:was ad:ded 167.57 mL o~
: concentrated 48% aqueous HBr o~er three minutes. :A
; :copious precipitate formed. The miture was ~tirred ~ 25 and cooled to 3C and the solids were filtered off ;~ ~ through a 3 L (M) porosity ~u~nel with ~ fritted disk. The sQlid wa~ washed with 1352 mL of i!ce cold ~ water in portions then dried with suction under :~ ~ - nitrogen and then overnight at 60C under high : ~ 3a ~acuum. The isol~ted product weight was 142.9 grams t 94.82% yield/97.91 wt.% pure which when eorrected for ~ sa~ple u~ed in ~PLC reaction monitoring calculates to : ' .j',9, W~93/02036 PCT/US92/~901 2 1 1 ~ 7 24 -;; 143.7 grams/95:.4% yield. The product contained . residual ~tarting material of 0.14 HPLC area % and no .; detectable water by KF titration. The following ~~ impurities were detec~ed by ~PLC i~ the crude s 5 product: succi~imide: 0.573 area X; 3,5-dibromo 2,6-dimethoxybenzoic acid: 0.146 area ~/O; and .. 315-dibromo 2-hydroxy-6-methoxybenzoic ~cid: 0.OlZ
. ~ - area %.
.' ~ .
~ethod D: Pxeparation U~ing N-Bromoæuccinimide and Aq~ous P~tassium ydro~ide _ :
- A 500 mL round-bottomed 4-~ecked 24/40 ST.
reaction ve~sel, fitted with a mechanical ~tirrer and digit~l thermomet~r~, was charged:wi~h 8.0 grams of : powdered~2,6-dimetho~ybenzoic acid (Aldrich ~9%, ; 43~t473 mmol)~, 7.02~gm. potas:sium:hydroxide (86.8%
pure , 2 . 5 ~ equiY ., ~108.68 mmol) and 4S mL of water.
:The reaction mi~ture wa~ ~tirred and heated to 50C
to~olubulize the mi~ture. The mixture~was cooled to ~1C~ and~9.~38 gram~of powdered N-bro~osuccinimide, (99% pure,:~l.2 equi~.) was added to the reaction ixture. The:~tempsrature of the reaction mixture:
ro~e to 10C:and then the cooling bath wa~ remo~ed.
The r~ac~ion was warmed to room temperature and was 5~ ~stirred for a total of 27 hours. The r~eaction at this point gave a wPakly positi~e SPT. ;The reaction mixture was treated with 1 gm of æodium sulfite which resulted in the reaction mixture giving a negative - SPT. The reaction mixture was cooled to 0 - 1C and 3~ wa~ acidified with 15.95 mL of concentrated ~`~ hydrobromic acid ~add~d in portions o~er 1 min.).
The copious p~ecipitatcd reaction mixture wa~

: ' , ~ , ~ ':

, ~

WO 93/~2036 PCI/lJS92/0!;901 ~ ;~
21-~127 .,, .; "

- 25 - ;~
'.'.'` ''."
f iltered cold through a f ritted glass suction funnel. The filtrate~was used to aid in the transfer, th~en the precipitate ~as washed with 125 mL ; .-:
: of ice cold lN aqueous ~Br in portions, then ~uction S dried under ~itrogen. The precipitate was dried overnight a~ 60-C. The product weighed 10~5 gm whsch ;:~:
by ~PLC analysis contain~d 1. 9 wt .% o~ unreact~d . :
starti~g material/2.:6% yield and 90.1 wt.~/. of the desired product (83.3% yd.~ and no detectable water :~10~ by~KF~titration.

Method E: Preparati:on:Using Dibromodimethylhydantoin ~:~

Z,6-Dimethoxybsnzoic acid (99.:0;g~, 538 15~ mmols) is~stirred~with 500 mL of water at r:oom : ~;
temperature, followed~by the addition:of~5N~aqueous~
NaOH~ llO:~;mL, 550~mo~1). The~resulting orange : :~
:solution i:s cooled;t~::20C by:a cold wate;r bath and DBDM~(80.2 g,~272.~1~mmols) is~ a~dded in:~portion~:over ~
2~0~ 5 min.~while mainta`in:ing the::in~ernal temperature~at :: I :
<25~C~ :Thé mixture uas:~allowed to~st:ir~at~20-~5C~
for 4.`~5~hours and worked up~as describe:d:~i:n~Method A
he~r:einabove. :The~:G~rude~product was recrystallized~
rom~aqueous ethanol:to p~ovide 122.6 g of the ~ -:
5~de~sired~product. ~:Analytical eva:luatîon of the~
product and the mother liquoræ from the :
re~c~ystalli~atlon:i~dicated;a 9fO.0%:assay yi~1d of , ;:~
the 3-bromo-2,6-dimethoxybenzoic acid and a 2.1% ~
: assay yield~of 3,5-d:ibromo-2,6-dimethoxybenzoi;c acid.
30 :
:
, ~: :,.................................................................. . .
:, , , `:
~, ~ ' .'.'`
. . , '`

,, wos3/o2o36 PCT~US92/OS~01 ~ ~

2 ~ 1 1 2 7 - 26 - ~
' `' " ' ~=~_ '''' ' (Illustrati~e of Prior Process) A 2 liter round-bottomed flask wa~ charged with 72 gram'~. of 2,6-dimetho~ybenzoic acid (99%, ~:~
391.2 mmol) and 237 gxams of dio~ane. The solution was cooled to 15 and bromine (62.11 grams, 99.~%, 1 eguiv.) w s added dropwise over 2 hours while the temperature was maintained at 17 ts 19C. The ~;reacti~n mixture was stirred at 20C for 2 hour~
lo ~hen 50 mL of water~ was added dropwi~e over ~0 mins.
to the mixture. The mixture was then cooled to 15C
and an additional 834 mL of water was a;dded dropwlse over a 2 hour period. The reaction mixture was aged at 15C for 3 houis~and~the;solid whi~h ~ormed wa~
5 ~ collected by filtration and washed with 60~mL of water. ~The solid~was dr~ied under high~ Yacuum at 70C
for 12 hour~ tQ prQYide 87.9 g 0~ the crude desired product (93.0% pure~,~ 79% yield). The following -;~
impur~ities were detected by ~PLC in the crude ~reaction product: 3,5-dibromo-2,6-dimethoxybenz~ic acid: 0.385~area~%;~3,5-dibromo-2-hydroxy- ;
- ~ 6-methoxybenzoic acid: 4.05 area %;~and ~ ;~
3-broms-2-hyd~oxy-6-methoxy benzoic~acid: 2.91 area~%.

25~ ~ ~ XAMPLE 2 Svnthesis o~ 2-BrQm,o-3~4.5-trim~thoxy~nzoi~ Acid U~ing the procedure described herein above -`
~ in E~ample 17 Method E, 3~4,5-trimet~oxybenzoic acid ;~ 3~ was broml~ated with DBDMH to provide the following ; `~
,..
xe~ul~ (a~say yields) after reac~ing ~or 25 hours at `. ~
" . , ~Z~" C: ~ ~

: ~ .
,:~
.:
~ ' ~
; ~:

W093/02036 pcT/us~2/o~snl - 21~ ?127 : ~;

2-bromo-3,4,5-trimethoxybenzoic acid: 91.1Z;
3,4~5-trimethoxybenzoic acid: 3.7%;
2,6-dibromo-3,4,5-trimethoxybenzoic acid: 2.0%.

~Q~

Synthesis of ~ Q~Q=~ dimç~ho~y~nzoic Acid : ~sing the procedure described herein above in Example 1, Method ~, 2,3-dimethoxybenzoic acid was ::
brominated with DBDM~ t:o provide the following results (assay yield~) af~er reacting for 22 hvurs at. ~.
20-25C:
6~bromo-2,3-dimethoxybenzoic acid: 90.3%; .
2,3-dimethoxybenzoic acid: 7.7%;
15~ ~ 5-bromo-2,3-dimethoxybenzoic acid: 2.5%.

AMPLE 4 ~

yI~he~ f ~-BromQpiperonYlic ~cid : ~;
20 ~ sing the~procedure descrlbed:her~ein abo~e ~-in Example l$ Method E, plperonylic acid wa6 brominatcd with DBDME to provide the ~ollowing r:esult~ ~a~say yields) af~er reacting for 22 hou~s at ~::: : 20-2~C~
2-bromopiperonylic acid: 86.0%;
, pipero~yIic ~cid: 7.7%. :~

~5~ is of 5--Bromo-2-methoxYbenzoic :Acid . ..~::
: Method A: ~Æ~-ination with ~-Br~mosuc~inimide and ~
: ~ '' '~;

.

2112127~ - 28 - ~
, o-Anis~c acid (4.56g, 30 mmols) was charged :~
~ ~ in a 250 mL flask and a æolution:of 2.64g (66 mmol~
j of NaO~ i~ 47 mL of water was added. The anisic acid :~
~as dissolved wi~h stirring and the ~olution then `- 5 cooled ~o 0 to 5C with an ice/methanol bath. ~BS
(6.41g, 36 mmol) was added in portions~tc the reac~ion fla~k and after the addition was complete the reactio~was allowed to warm to room ~: :temperature. The: reaction was stirred at room :~;
lo ~ tempesature for 48 hours and was monitoréd ky : ~-: analytical LC during this time. At the end of the 48 : : hou~s another 002: equiY~ (5 mmol) of NBS was addedjto :~
the r~eaction:~mi~~ure~ and the reaction mi:~ture was sti:rréd:at room temperature for an additional 7 5:~ hour:s.~ Workup~as~ describe~d i:n Example:l, Method A, : -.
p~rovid;ed~:7.34g~of~a~:solid (~98.5%~pure by:HPLC, 1~.5%
; of~ :Bolid: is~unr~a~ted~EtartiIlg material;; 93% yield.3 The~f~iltr~ate;~f~rom~the solid contains anot:her 2% yield of brominated~product~

Method B: rominat:ion with Dibrom~dimethvlh~dantoin nd::NaQ~
Using~th~e~procedure described her;ein~above:
: in Example l,~Met~od E, o-anisic a~i~ was bromina~ed 25~ with DB ~ ~o provide the following resultæ (a~say~
yields) af~er~:reacting for 18 hours at 20-25~C:
5-~romo-2-metho~ benzoic ac,i,d: 98%. j .
he isolated prc~duct contains 0 . 3 wt% of unreacted product, :; ~
,,~ :~ :
",, :
. :
:~' :: : ~ :
:
~ :~

Claims (10)

WHAT IS CLAIMED IS:

1. A process for the preparation of a compound having the formula IV:

IV
or an alkali salt thereof;

wherein:

R1, R2, R4, and R5 are independently selected from::
(a) hydrogen, (b) C1-C6-alkyl, : :
(c) C1-C6-alkoxy, (d) -OH, (e) -CO2H, (f) -CO2(C1-C6-alkyl), (g) -N(C1-C6-alkyl)2, or R1, R2, R3, R4, or R5 on adjacent ring carbons may be combined to form a -O-(CH2)n-O- residue;

provided that at least one of R1, R2, R4, or R5 is -CO2H;

R3 is C1-C6-alkoxy or -N(C1-C6-alkyl)2, or R2 and R3 or R3 and R4 are combined to form a -O-(CH2)n-O-residue; and n is 1 to 3;

which comprises:
treating an aromatic compound of the formula V:

V
in an aqueous alkali solution with a brominating agent selected from:
(a) N-bromosuccinimide, and (b) 1,3-dibromo-5,5-dimethylhydantoin;

at a temperature and for a length of time sufficient to optimally convert the compound of formula V to the compound of formula IV or a salt thereof; and then optionally treating the reaction mixture with an acid to afford the compound of formula IV.

2. The process of Claim 1 wherein the amount of the brominating agent employed is selected from a value in the range between 0.505 to 1.5 molar equivalents with respect to the compound of the formula V.

3. The process of Claim 1 wherein the brominating agent is N-bromosuccinimide.

4. The process of Claim 3 wherein the aqueous alkali solution is selected from a solution of sodium hydroxide in water or a solution of potassium hydroxide in water.

5. The process off Claim 1 wherein the acid is an aqueous acidic solution.

6. The process of Claim l wherein the brominating agent is 1,3-dibromo-5,5-dimethyl-hydantoin.

7. The process of Claim 6 wherein the amount of the 1,3-dibromo-5,5-dimethylhydantoin utilized in the process relative to the amount of compound V is selected from 0.505 to 0.55 molar equivalents amd the amount of alkali base in the aqueous alkali solution relative to the amount of compound V is selected from 1.01 to 1.1 molar equivalents.

8. A process for the preparation of a compound, having the formula IVa:
IVa which comprises:
treating a benzoic acid of the formula Va:

Va in an aqueous alkali solution with a brominating agent selected from:
(a) N-bromosuccinimide, and (b) 1,3-dibromo-5,5-dimethylhydantoin at a temperature and for a length of time sufficient to optimally convert the compound of formula Va to the compound of formula IVa or a salt of the compound of formula IVa; and then optionally treating the reaction mixture with an acid.

9. The process of Claim 8 wherein the brominating agent is N-bromosuccinimide.

10. The process of Claim 8 wherein the brominating agent is 1,3-dibromo-5,5-dimethyl-hydantoin.